Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Cancer is a leading cause of death in the United States. Treatments for metastatic cancer are generally limited, and include radiation, chemotherapy with non-specific cytotoxic agents, and therapy with drugs targeted at specific proteins that have been identified as marking cancer cells, and actively contributing to the aggressiveness of cancer growth. Taking metastatic colorectal cancer as an example, among the relatively limited drugs available for treatment of this disease, the DNA damaging agent irenotecan (a pro-drug for camptothecin), and antibodies (cetuximab, panitumumab) and small molecules (erlotinib, gefitinib) targeting the receptor tyrosine kinase (RTK) EGFR, an upstream regulator of the Ras pathway, have shown some efficacy (1-3). It is likely that improvement of therapies directed against EGFR and its family members (e.g., ERBB2/HER2/NEU, ERBB3/HER3) will be beneficial for treatment of numerous metastatic cancers, including those of breast, lung, and pancreas, as these proteins are often abnormally abundant or active in these tumors (e.g. 4,5), and EGFR-family targeting agents such as erlotinib and cetuximab have recently been approved for use in combination therapies in these cancers (1).
While combination of DNA damaging agents such as irenotecan and EGFR-targeting antibodies in the clinic, in some cases, produces substantial therapeutic benefit, in other cases, patients fail to respond. It is extremely likely that the failed response arises from secondary mutations in cancer cells that confer resistance to DNA damage, or relieve dependence of cells on EGFR: for example, mutations in K-Ras are becoming appreciated as a resistance factor for EGFR-directed therapies (6). In other cases, the sources of resistance or sensitivity are obscure (7).